Testosterone Promotes Prostate Cancer in Rats


Testosterone was found to be a weak complete carcinogen and a strong tumor prompter in rats, according to a researcher, who said that studies on the impact of testosterone therapy on cancer risk in aging men were "urgently needed."

They examined prostate tumor growth in intact male rats treated with slow-release testosterone implants alone, or testosterone implants, preceded by a single injection of the carcinogen N-nitroso-N-methylurea (MNU). Without the MNU, testosterone induced prostate tumors in 10% to 18% of the rats. With the MNU injection, there was 50% to 71% prostate tumor incidence, stated Maarten C. Bosland, PhD, of the University of Illinois at Chicago.

Even testosterone doses that did not elevate circulating levels of the hormone appeared to promote tumor growth, Bosland wrote in a brief report in Endocrinology.

Their findings led Bosland's group to call for retrospective and prospective studies that would examine the efficacy and safety of testosterone replacement therapy (TRT) used for reasons other than hypogonadism.

Sales of testosterone treatments to middle-age and older men for low-T have now reached over $2 billion annually.

"Testosterone has become a multibillion dollar a year industry, and we don't really know if these treatments do what marketers claim or if they are safe," Bosland told MedPage Today. "It is imperative that we do the studies in humans that are needed to answer these questions."

FDA Weighs In

The research comes just weeks after an FDA advisory panel voted to tighten the labeling of TRT in an effort to discourage their off-label use by men without clear evidence of hypogonadism, defined as having an absence or deficiency of testosterone due to documented testicular or hypothalamic/pituitary disease.

The panel also overwhelmingly voted to require drug companies marketing TRT products to conduct studies assessing their cardiovascular risks. It also recommended against approval of the oral testosterone Rextoro.

Cardiovascular concerns arose in 2010 after a small placebo-controlled testosterone therapy trial in elderly men was stopped early due to an overall increase in cardiovascular adverse events. Several other observational studies also raised concerns about increased heart disease risk associated with TRT in both elderly and younger men.

In briefing materials published before the mid-September meetings, the FDA panel reiterated its support for TRT for patients with classic hypogonadism, but it questioned the use of the treatment "in aging men who have low serum testosterone concentrations for no apparent reason other than age, and who experience non-specific symptoms of aging that overlap with those of classic hypogonadism."

"Whether these symptoms are a clinical consequence of the age-related decline in endogenous testosterone has not been established, and therefore, the need to replace testosterone in these older men remains debatable," the panel noted.

TRT and Prostate Cancer Risk

There have also been concerns that TRT increases prostate cancer risk in otherwise healthy men, but this has not been well studied, Bosland noted.

"The potential of testosterone treatment to increase risk of prostate cancer, an androgen dependent malignancy, has been raised repeatedly," he wrote in Endocrinology, adding that "conclusive data on its safety for the prostate are lacking, probably in part because large scale testosterone therapy is a recent phenomenon and prostate cancer is a notoriously slow developing disease."

He further noted that 5-alpha-reductase inhibitors have been shown to significantly reduce prostate cancer risk in large clinical trials, suggesting that androgens enhance growth and progression of the cancer.

No fewer than five previously published studies in rats have shown that testosterone implants induced a low incidence of prostate adenocarcinomas, Bosland wrote.

His study involved male (Wistar CpB:WU) rats treated with slow-release Silastic implants of testosterone at doses that increased circulating levels of the hormone in a dose-related fashion with or without a preceding injection of MNU.

Two separate experiments were conducted, one with one or two implants after MNU (experiment A) and one with two or four implants with or without preceding MNU injection and control groups given empty implants or only MNU (experiment B).

The rats were euthanized when moribund or at the end of experiments (72 weeks after MNU in experiment A; 95 weeks in experiment B). Silastic tubing implants were also placed in three experiments with rats not treated with cyproterone acetate, testosterone propionate, and MNU. These rats were euthanized after 4-20 weeks.

Circulating testosterone was elevated after 4 weeks of treatment with Silastic implants in a dose-dependent fashion (dose number of 3-cm-long implants). One implant did not increase testosterone, two implants increased testosterone by close to two-fold, three implants by almost four-fold, and four implants by nearly six-fold.

MNU without subsequent testosterone treatment did not cause prostate cancer, whereas testosterone treatment without MNU induced prostate carcinomas in 10%-18% of animals (P=0.06 and P=0.02, respectively, compared with controls).

However, the addition of MNU to long-term testosterone treatment markedly increased prostate cancer incidence in all animals, including those that received only one implant (57% prostate cancer incidence), even though this dose did not increase circulating testosterone.

"Prostate cancer incidence was maximally elevated (67%-71%) with two implants (P<0.0001 for difference with MNU alone; one sided Fisher exact test)," Bosland wrote, adding that the dose this dose increased circulating testosterone two- to three-fold.

Tumor incidence did not further increase when four implants were used, even though circulating testosterone levels increased to six-fold control levels. There was also a trend toward a lower prostate tumor incidence with the highest testosterone doses, compared with two implants, but this was not statistically significant.

Multiple dorsolateral prostate carcinomas (two to three 3 per rat) were found in four or five animals (17%) in groups given MNU plus testosterone without differences between groups receiving different androgen doses.

TRT and ERT: Similarities and Differences

Bosland noted that previous studies of cancer risk associated with testosterone treatments in humans have been too small and too short to determine if the therapy is safe.

"I would urge caution. I would not take this treatment and I would not recommend it to anyone else until adequate studies have been done," he said.

He added that the similarities between the dramatic increase in the use of testosterone in aging men and the use of estrogen replacement therapy (ERT) in menopausal and postmenopausal women a little more than a decade ago are hard to ignore.

Prior to the abrupt end of the Women's Health Initiative (WHI) study, estrogen therapy was widely viewed by both women and their physicians as a panacea for the prevention of age-related maladies.

The large, randomized, federally-funded prevention trial instead showed that estrogen plus progestin increased heart disease and breast cancer risk in the study cohort, while estrogen alone appeared to increase the risk of stroke and dementia.

Lisa Schwartz, MD, professor of medicine at The Dartmouth Institute in Hanover, N.H., told MedPage Today that while there are similarities between the rise of the two treatments, there are also differences.

"The big push for hormone replacement therapy in women came from the medical establishment after observational studies suggested that the treatment reduced heart disease," she said. "The big push for testosterone treatment has come from the drug industry, which has promoted the idea that 'low-T' is a common medical condition."

Schwartz, who co-wrote a 2013 editorial published in JAMA Internal Medicine, questioning the marketing of 'low-T' as a disease, noted that several recent studies, including one in men with type 2 diabetes, showed testosterone treatments to be ineffective.

"If there is no benefit, why would anyone take a drug that may have risks?" she asked. "Of course we need studies to determine if there are risks, but we also need studies to determine if there are benefits. We really don't know if [the age-related drop in testosterone] is associated with aging and disease or if it is nothing more than a lab test abnormality."